Uncontrolled diabetes mellitis (uDM) is a unique and well-defined rodent model for delineating the neuroendocrine mechanisms that control food intake. The hypothesis that neuronal systems in the arcuate nucleus (ARC) of the hypothalamus are regulated by hormones such as insulin and leptin that circulate in proportion to body fat mass has received strong support from studies using this model. Specifically, ARC neurons that promote increased food intake, such as the NPY/AgRP neuron, are activated by the effect of uDM to lower insulin and leptin levels. Similarly, ARC POMC neurons, which reduce food intake, are inhibited by these hormonal responses. Several observations suggest that the effect of uDM to increase food intake, known as diabetic hyperphagia, results at least in part from these ARC neuronal responses. The intracellular mechanism whereby insulin and leptin regulate ARC neurons is hypothesized to involve activation of the insulin receptor substrate-phosphatidylinositial-3-OH kinase (IRS-PI3K) pathway. A key hypothesis of the current proposal is that reduced PI3K signaling in ARC neurons results from deficient signaling by insulin and leptin and plays a critical role in their response to uDM. A related hypothesis is that reduced signaling via PI3K in ARC neurons mediates not only food intake stimulation, but also contributes to hyperglycemia by causing insulin resistance in peripheral tissues. Finally, new data from the investigator's laboratory suggests that the orexigenic gastric hormone ghrelin may also contribute to the hypothalamic response to uDM. Studies are proposed to 1) identify ARC neurons in which PI3K is activated by insulin treatment of uDM; 2) identify hypothalamic, behavioral (e.g., diabetic hyperphagia) and metabolic responses to uDM that are dependent on reduced PI3K signaling in the ARC; 3) determine whether the ability of insulin to reverse hypothalamic, behavioral or metabolic responses to uDM requires hypothalamic PI3K signaling; and 4) determine the contribution of elevated plasma ghrelin levels to manifestations of uDM. This work will fundamentally advance our understanding of the neuroendocrine control of food intake and glucose metabolism, and has the potential to identify new, neuronal factors that influence insulin requirements in patients with diabetes.